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Pentoxifylline inhibits FMLP-induced macromolecular leakage
K Nakagawa1, F N Miller, A W Knott
1Department of Surgery, University of Louisville, Kentucky 40292, USA.
The American Journal of Physiology
|July 1, 1995
Summary
Pentoxifylline (PTXF) effectively reduces acute inflammation caused by N-formyl-methionyl-leucyl-phenylalanine (FMLP) in microcirculation. This effect is mediated by increased cyclic adenosine monophosphate (cAMP) and is independent of histamine.
Area of Science:
- Pharmacology
- Microcirculation Physiology
- Inflammation Research
Background:
- The chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) is a potent inducer of acute inflammatory responses.
- Pentoxifylline (PTXF) is a xanthine derivative with known anti-inflammatory properties, but its precise mechanisms in microvascular inflammation require elucidation.
Purpose of the Study:
- To investigate the in vivo effects of PTXF on FMLP-induced acute inflammatory responses in rat microcirculation.
- To determine the role of histamine and intracellular cyclic adenosine monophosphate (cAMP) in PTXF's inhibitory actions.
Main Methods:
- Intravital microscopy of rat cremaster muscle to assess microcirculatory inflammatory parameters.
- Quantification of macromolecular leakage using fluorescein isothiocyanate conjugated to bovine serum albumin.
- Evaluation of leukocyte-endothelium adhesion and blood flow changes.
Main Results:
- FMLP significantly increased macromolecular leakage, leukocyte adhesion, and decreased blood flow.
- PTXF dose-dependently inhibited FMLP-induced responses but not histamine-induced leakage.
- A cAMP analogue mimicked PTXF's effects, suggesting a cAMP-mediated mechanism.
Conclusions:
- FMLP triggers acute inflammation via neutrophil activation, independent of histamine.
- PTXF inhibits FMLP-induced microvascular inflammation by increasing intracellular cAMP levels.
- Elevated cAMP modulates endothelial, smooth muscle, and neutrophil functions, thereby reducing inflammation.